The farnesoid X receptor (FXR), the peroxisome proliferator-activated receptor xcex1 (PPARxcex1), and the liver X receptor xcex1 (LXRxcex1) are members of a superfamily of approximately 150 proteins that bind to cis-acting elements in the promoters of their target genes and modulate gene expression in response to hormone activators or ligands. For many of these receptors, the activators are known, while for others, termed xe2x80x9corphan receptors,xe2x80x9d the activators are unknown. Furthermore, some of these receptors bind to their target genes as dimers consisting of two molecules of the same receptor (homodimers), while others bind as dimers consisting of one molecule each of two different receptors (heterodimers). Prominent among the latter are nuclear receptors that require heterodimerization with the retinoid X receptor (RXR), as disclosed in Yu et al. Cell 67:1251-1266 (1991). Members of this group include the vitamin D receptor, the thyroid hormone receptor (T3R), the retinoic acid receptor (RAR), FXR, the peroxisome proliferator-activated receptors (PPARs) and LXR xcex1.
FXR was first reported by Forman and coworkers, Forman Cell 81:687-693 (1995). This receptor is a protein having a relative molecular mass (Mr) of approximately 54,000, and is a vertebrate transcription factor regulated by intracellular metabolites. The receptor is activated by certain farnesoids, i.e., farnesol, compounds derived from farnesol, and/or compounds similar in structure to farnesol. These farnesoids include farnesol, farnesal, farnesyl acetate, farnesoic acid, geranylgeraniol and juvenile hormone III.
FXR is a nuclear receptor thought to be involved in negatively controlling the expression level of cholesterol 7xcex1-hydroxylase (cyp7a), the rate-limiting enzyme involved in the oxidative metabolism of cholesterol into bile acids. As such, modulators of FXR activity will find utility in diseases associated with abnormally high or low cholesterol levels. Of particular value will be FXR antagonists, which block the negative feedback downregulation of cyp7a expression produced by certain cholic acids, the endogenous ligands for FXR. FXR is also involved in controlling the synthesis of isoprenoid derivatives (including cholesterol), and the proliferation of certain types of cancerous cells, such as those derived from colon carcinomas. Additionally, since FXR forms heterodimers with RXR in some cell types, modulation of the level of FXR activity in a cell has a wide range of effects on a variety of biological processes which are mediated by RXR or other RXR-interacting proteins such as PPARxcex3 and PPARxcex1. These other biological activities include, among others, obesity, diabetes, lipid associated disorders, cancer, inflammatory disorders, disorders involving a disrupted or dysfunctional epidermal barrier, and various other metabolic disorders. Modulators of FXR, both agonists and antagonists, will find utility in treating one or more of these diseases.
PCT Publication No. WO 00/40965, which is incorporated herein by reference, describes methods and compositions that are useful for modulating cholesterol levels in a cell and methods for identifying compounds that can be tested for ability to modulate cholesterol levels in mammals. These methods involve analyzing the effect of a test compound on the binding of FXR to an FXR ligand. Such ligands include, for example, bile acids, coactivators, and corepressors. The methods and compositions involve modulating FXR-mediated expression of genes involved in cholesterol metabolism.
Despite the advances made by WO 00/40965, there is a need in the art for new FXR modulators, both antagonists and agonists, to be used for a variety of indications. The present invention remedies this and other needs.
Atherosclerosis is a leading cause of death, myocardial infarctions, strokes, peripheral vascular disease and cardiovascular disease. One of the major contributing factors to atherosclerosis is hypercholesteremia. By modulating FXR-mediated expression of genes, using FXR modulating compounds, it is possible to mitigate and thereby treat hypercholesterolemia.
The present invention provides compounds, pharmaceutical compositions and methods that modulate FXR. The invention also provides methods of using the compounds and compositions for the treatment of conditions and disorders mediated by FXR, such as atherosclerosis, diabetes, obesity, dyslipidemia, hypercholesterolemia, hypertension, hyperlipidemia and hyperlipoproteinemia, certain inflammatory conditions and cancer.
As such, in certain aspects, the present invention provides compounds of Formula I:
B1xe2x80x94L1xe2x80x94A1xe2x80x94L2xe2x80x94B2xe2x80x83xe2x80x83I 
In Formula I, A1 represents a divalent group selected from the following: alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene, or A1 represents a single or double bond linking L1 and L2.
L1 and L2 are each independently selected from the following group of divalent radicals: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)N(R1)xe2x80x94, xe2x80x94O-alkylene-; xe2x80x94S-alkylene-, xe2x80x94N(R1)-alkylene, xe2x80x94C(O)-alkylene, xe2x80x94C(O)N(R1)-alkylene, xe2x80x94C(O)xe2x80x94O-alkylene, alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, arylene, heteroarylene, heterocycloalkylene, and heterocycloalkenylene.
B1 and B2 are each independently selected from the group: alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkenyl.
In some aspects, L1 can be additionally linked to B1 via a group X1 to form a 5-9 member ring. In a similar manner, L2 can be additionally linked to B2 via a group X2 to form a 5-9 member ring.
X1 and X2 are each independently selected from: a single bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)N(R2)xe2x80x94, xe2x80x94O-alkylene, xe2x80x94S-alkylene, xe2x80x94N(R2)-alkylene, xe2x80x94C(O)-alkylene, xe2x80x94C(O)N(R2)-alkylene, and xe2x80x94C(O)xe2x80x94O-alkylene.
R1 and R2 are each independently selected from: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, or (heteroaryl)heteroalkyl.
In another aspect, the present invention provides FXR modulators of Formula II: 
In Formula II, A2 and A3 are each independently selected from: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl, aryl(heteroalkyl), or (heteroaryl)heteroalkyl.
B3 is selected from the following: -hydrogen, -alkylene-C(O)R3, xe2x80x94C(O)R3, alkylene-C(O)N(R3R4), xe2x80x94C(O)N(R3R4), alkylene-S(O)nN(R3R4), xe2x80x94S(O)nN(R3R4), alkylene-N(R3R4), alkylene-OR3, and xe2x80x94C(O)OR3.
R3 and R4 are each independently selected from: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl, aryl(heteroalkyl), and (heteroaryl)heteroalkyl.
X is C, S, or N.
The subscript p is an integer from 0-2.
In still another embodiment, the present invention provides FXR modulators of Formula III: 
In Formula III, A4 is selected from the following: xe2x80x94C(O)R5, xe2x80x94C(O)N(R5R6), xe2x80x94S(O)nN(R5R6), -alkylene-N(R5R6), -alkylene-OR5 and xe2x80x94C(O)OR5.
L3 and L4 are each independently selected from the following divalent radicals: a single bond, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)pxe2x80x94, and alkylene, wherein the subscript p is an integer from 0-2.
B4, B5 and B6 are each independently selected from: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, fused-benzoheterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.
Alternatively, B4 and B5 join to form a divalent arylene, heteroarylene, alkylene, or cycloalkylene linkage between L3 and L4.
X3 and Y are each independently a trivalent nitrogen atom or a trivalent or tetravalent carbon atom.
R5 and R6 are each independently selected from: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.
In still yet another aspect, the present invention provides FXR modulators of Formula IV: 
In Formula IV, A5 is selected from the following divalent linkages: xe2x80x94C(O)xe2x80x94, -alkylene-, xe2x80x94S(O)nxe2x80x94, xe2x80x94C(O)N(R12)xe2x80x94, xe2x80x94S(O)2N(R12)xe2x80x94, -alkylene-N(R12)xe2x80x94, -alkylenexe2x80x94Oxe2x80x94, or xe2x80x94C(O)Oxe2x80x94.
L5 and L6 are each independently selected from the following group of divalent radicals: a single bond, xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94, and alkylene, wherein the subscript n is an integer from 0-2.
B7, B8, and B9 are each independently selected from: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, benzoheterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.
Alternatively, B7 and B8 join to form a divalent arylene, heteroarylene, alkylene, or cycloalkylene linkage between L5 and L6.
Z is selected from the following divalent linkages: alkylene, heteroalkylene, cycloalkylene, or heterocycloalkylene.
X7 and Y1 are independently a trivalent nitrogen atom or a trivalent or tetravalent carbon atom; and
R12 is selected from: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, aryl(heteroalkyl), (heteroaryl)alkyl, and (heteroaryl)heteroalkyl.
In yet another aspect, the present invention provides FXR modulators of Formula V: 
In Formula V, A6 and A7 are each independently selected from: arylene, heteroarylene, cycloalkylene, or heterocycloalkylene.
B10 represents: aryl, heteroaryl, arylalkyl, (heteroaryl)alkyl, alkyl, cycloalkyl, cycloalkenyl, heteroalkyl, heterocycloalkyl, or heterocycloalkenyl.
L7, L8, and L9 are each independently selected from: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R13), xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, alkylene, xe2x80x94O-alkylene, xe2x80x94S-alkylene, xe2x80x94N(R13)-alkylene, xe2x80x94C(O)-alkylene, xe2x80x94C(O)N(R13)-alkylene, xe2x80x94C(O)xe2x80x94O-alkylene, a single bond, or a double bond,
X8 is selected from the following trivalent radicals: N, CR13; and
R13 is selected from: hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, arylalkyl, or (heteroaryl)alkyl.
Unless otherwise indicated, the compounds provided in the above formula are meant to include pharmaceutically acceptable salts and prodrugs thereof.
In addition to each of the aspect of the invention provided above, the present invention further provides pharmaceutical compositions containing one or more members of the classes of compounds above in admixture with a pharmaceutically acceptable carrier or excipient. Still further, the invention provides methods of using the compounds described herein for the treatment of FXR-mediated conditions and disorders as well as the modulation of cyp7a expression levels in mammals. FXR-mediated conditions and disorders include, but are not limited to, atherosclerosis, peripheral vascular disease, cardiovascular disease, hypercholesteremia, cholesterolemia, obesity, diabetes, inflammatory conditions and diseases associated with abnormally high or low cholesterol levels.
In other embodiments, the compounds of the present invention are administered in combination with certain other compounds of the present invention xe2x80x9cin combination therapyxe2x80x9d or in combination with other therapeutic compounds.
In yet another embodiment, the present invention provides the use of a compound of Formulae I-V for the manufacture of a medicament for treatment of an FXR mediated disease or condition.
These and other aspects will become more apparent when read with the accompanying diagram and detailed description, which follows.